This proposal's broad long-term objectives will address major obstacles to advancing therapeutics and prevention in Alzheimer disease (AD): 1-pharmacogenomics, 2-the molecular targeting of pleiotropic mechanisms implicated in pathogenesis and 3- identifying biomarkers predicting drug efficacy. Despite their limitations, animal models have been fundamental for identifying promising clinical approaches, including the A[unreadable] vaccine and supplementation with omega-3 fatty acids (particularly docosahexaenoic acid, DHA), but success of these approaches may depend on genetic risk (pharmacogenomics) and efficacy may not be robust, if initiated too late. Multiple drugs (cocktails) better target the pleiotropic mechanisms contributing to AD. In this proposal, we focus on ApoE4, the major genetic risk factor for AD. Emerging clinical data suggest a differential ApoE isoform-dependent response to NSAIDs, antioxidants (Hayden et al., 2007;Szekely et al., 2008), DHA or fish (Whalley et al., 2008) and the amyloid vaccine (Salloway et al., 2009). This proposal fulfills a major knowledge gap since, despite the huge impact of ApoE4, preclinical pharmacogenomics studies have not been undertaken. We will characterize the impact of ApoE4 on treatment responses to DHA and determine whether efficacy can be improved by combining DHA with the antioxidant a lipoate (found in vegetables like spinach) or the natural anti-inflammatory drug curcurmin from turmeric root, a combination which we have found to work synergistically and has shown large benefits in APP and tau models, but not tested in relation to ApoE isoform. To overcome these obstacles, we utilize a novel animal model with targeted replacement for human ApoE (isoforms E2, E3 and E4). The advantages of this novel model are that it has synapse loss and cognitive impairment within one year, enabling one to evaluate ApoE isoform dependent effects on treatments. We test passive A[unreadable] vaccination as a "positive control" and to further validate the model since clinical data suggests optimal efficacy only in non ApoE4 carriers. Aim 1) Determine the impact of ApoE4 genotype on limiting DHA protection. Aim 2) Determine if limited DHA efficacy (especially with ApoE4 carriers) is improved with lipoate, curcumin or the combination, Aim 3) Identify ApoE isoform-dependent plasma biomarkers that our data suggest reflect synaptic loss, Aim 4) Identify plasma biomarker responses, that predict treatment efficacy, including immunotherapy. Innovations include identification of novel surrogate biomarkers, improved prevention for ApoE4-carriers and the novel characterization of an animal model suitable for investigating ApoE-genotype treatment interaction. In summary, we address critical barriers to progress in the field of translation by addressing pharmacogenomics, not only challenging existing paradigms for planning future AD prevention programs, but also identifying novel neurodegenerative-dependent plasma biomarkers, essential to overcome inadequate endpoints for AD prevention trials. PUBLIC HEALTH RELEVANCE: There are major barriers to developing cost-effective safe practical ways of preventing AD, a vital US interest since, in addition to the enormous emotional burden of Alzheimer disease (AD), its exponentially growing incidence and prevalence present a pending catastrophic economic burden at both national and international levels;but ironically reducing the economic burden of AD demands that we must first pay high costs for prevention trials, that can easily reach from $25 to 50 million per drug for even a short prevention trial (e.g. 6 years). Another major obstacle is that clinical data, suggesting success with some of the promising and safe treatments (e.g. the dietary omega-3 fatty acid DHA) appears ApoE genotype-dependent (pharmacogenomic), but the basic science has so far failed to investigate and elucidate the reasons for these findings, contributing to limiting success of future trials. This proposal attempts to overcome these major obstacles for DHA and other Alzheimer prevention methods by improving candidate intervention testing paradigms that incorporate human ApoE isoforms into the AD models to determine whether drugs that are poorly efficacious in ApoE4 carriers can be improved by safe cocktails that provide additional targeting of inflammation and oxidative damage (pleiotropic), in addition to identifying sensitive plasma biomarkers reflecting synaptic damage and linked to memory deficits;these biomarker tools will be extremely helpful to predict intervention efficacy during the prodromal period prior to cognitive decline.